Design,synthesis and biological evaluation of 8-(2-amino-1-hydroxyethyl)-6-hydroxy-1,4-benzoxazine-3(4H)-one derivatives as potent β2-adrenoceptor agonists |
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| Institution: | 1. Department of Medicinal Chemistry, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China;2. Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China;3. Department of Pharmacology, School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China;1. Center for Biomaterials, Korea Institute of Science & Technology (KIST School), Seoul, Seongbuk-gu, 02792, Republic of Korea;2. University of Science & Technology (UST), Daejeon, Yuseong-gu, 34113, Republic of Korea;3. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, Giza 12566, Egypt;4. Medicinal & Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre (NRC), Dokki, Giza 12622, Egypt;5. Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul, Republic of Korea;6. College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea;7. Center for Neuro-Medicine, Korea Institute of Science & Technology (KIST School), Seoul, Seongbuk-gu, 02792, Republic of Korea;8. Department of Beauty Science, Hanseo University, Seosan 31962, Republic of Korea;1. Faculty of Science, Department of Chemistry, Rhodes University, Grahamstown, 6140, South Africa;2. Faculty of Science, Department of Biochemistry and Microbiology, Rhodes University, Grahamstown, 6140, South Africa;3. Biomedical Biotechnology Research Unit, Rhodes University, Grahamstown, 6140, South Africa;4. Centre for Chemico- and Biomedicinal Research, Rhodes University, Grahamstown, 6140, South Africa;5. Division of Clinical Pharmacology, Faculty of Medicine, University of Cape Town, Observatory, Cape Town, 7925, South Africa;6. Division of Pharmaceutical Chemistry, Faculty of Pharmacy, Rhodes University, Grahamstown, 6140, South Africa;1. Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-032, Japan;2. Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577, Japan;1. College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea;2. Natural Products Research Institute, Seoul National University, Seoul 08826, Republic of Korea;3. Pharmaceutical Research Institute, Seoul National University, Seoul 08826, Republic of Korea |
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| Abstract: | A series of β2-adrenoceptor agonists with an 8-(2-amino-1-hydroxyethyl)-6-hydroxy-1,4-benzoxazine-3(4H)-one moiety is presented. The stimulatory effects of the compounds on human β2-adrenoceptor and β1-adrenoceptor were characterized by a cell-based assay. Their smooth muscle relaxant activities were tested on isolated guinea pig trachea. Most of the compounds were found to be potent and selective agonists of the β2-adrenoceptor. One of the compounds, (R)-18c, possessed a strong β2-adrenoceptor agonistic effect with an EC50 value of 24 pM. It produced a full and potent airway smooth muscle relaxant effect same as olodaterol. Its onset of action was 3.5 min and its duration of action was more than 12 h in an in vitro guinea pig trachea model of bronchodilation. These results suggest that (R)-18c is a potential candidate for long-acting β2-AR agonists. |
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| Keywords: | Asthma COPD Isoprenaline Salmeterol Olodaterol |
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